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Lixte Biotechnology Holdings, Inc.

248 Route 25A, No. 2

East Setauket, New York 11733

October 8, 2013

VIA EDGAR AND FACSIMILE

Scot J. Foley

U.S. Securities and Exchange Commission

Division of Corporate Finance

100 F Street NE

Washington, DC 20549

    Re:
    Lixte Biotechnology Holdings, Inc.

    Annual Report on Form 10-K for the Fiscal Year Ended December 31, 2012

    Filed March 15, 2013

    File No. 000-51476

Dear Mr. Foley:

This is in response to your letter to the
Company of September 13, 2013.

We have reproduced below in bold face the
text of your comments, followed by our responses. The numbered paragraphs below correspond to the numbered paragraphs in your letter.

Item 1, Business

Company Overview, page 4

1.	Please disclose the material terms
of your collaboration agreement with the National Cancer Institute. Your description should include, as may be applicable:

 · Nature of the collaboration;

 · Material payment provisions including initial, annual, milestone or royalty provisions;

 · Other material rights and obligations of both parties; and

 · Duration, term and termination provisions.

Please also file the collaboration agreement
as an exhibit to your next quarterly report on Form 10-Q and incorporate the exhibit by reference to your next Form 10-K. If you
believe that this agreement is not required to be filed pursuant to Item 601(b)(10) of Regulation S-K, please provide us with an
analysis supporting this conclusion.

Scot J. Foley

U.S. Securities and Exchange Commission

October 8, 2013

Page 2

COMPANY RESPONSE:

The Company will modify the disclosure in
its filings regarding the NExT program to make it clear that there was no binding agreement, payment requirements or other material
obligations between the parties. Accordingly, no exhibit is required to be filed pursuant to Item 601(b)(10) or any other exhibit
item. The proposed disclosure is as follows:

On September 17, 2010, the National Cancer
Institute (NCI) Experimental Therapeutics (NExT) Program Senior Advisory Committee (SAC) approved a collaboration by the NCI with
the Company for clinical evaluation of LB-100, one of the Company’s drug compounds. This collaboration is a milestone-based
approach in which NCI will first confirm studies of the LB-100 compound in an animal model of glioblastoma multiforme, the most
common form of brain tumor of adults, and conduct an initial exploratory toxicology study in an animal model. At milestone intervals,
the SAC will re-evaluate project progress before considering assignment of additional support and resources to this project. As
noted below, the NExT group advised the Company on several aspects of the process of pre-clinical characterization of LB-100 needed
for submission of an IND and carried out an initial toxicological study of LB-100 in rats. This study was used to guide the subsequent
formal toxicology studies based on good laboratory practice (GLP) completed in rats and dogs by the Company with a contract research
organization. The Company subsequently conducted its own GLP toxicity studies and submitted an IND for a clinical trial of LB-100,
which acknowledged the early assistance of the NExT program in planning the design of animal studies.

The NExT program of the NCI is a unique
partnership with the NCI to facilitate oncology drug discovery and development. The program is not a grant or a contract, but provides
access to the NCI’s drug discovery and preclinical development resources, including expert advice concerning the various
requirements for bringing a new compound to initial clinical trial. Participation in the NExT program is via a competitive application.
The Company was admitted to the program in September 2010. The Company received advice as to how to proceed with pre-clinical development
of its lead compound LB-100 and the NCI performed one rodent toxicology study with LB-100. The Company was not responsible for
any costs or payments, and neither party obtained or incurred any material rights or obligations. As is standard for the NExT program,
there was no specific agreement, other than to limit support to pre-clinical development pending validation of anti-tumor activity
in a specific tumor model. Activity deemed less than sufficient to warrant extension of NExTsupport toward clinical development
led to termination of the Company’s participation in the program on July 21, 2011. The Company subsequently carried out the
pre-clinical studies for and obtained an IND from the FDA to study LB-100 in a Phase I clinical trial.

Scot J. Foley

U.S. Securities and Exchange Commission

October 8, 2013

Page 3

Intellectual Property, page 5

2.	Please expand this disclosure to
list each of your material patents and indicate the product candidates to which they relate and the indications they are intended
to treat, the jurisdictions in which the patent applications were filed, their expiration dates, and the type of patent protection,
e.g. composition of matter, use or process.

COMPANY RESPONSE:

The Company will expand its disclosures
in its filings regarding its patents as follows:

The Company’s products will derive
directly from its intellectual property, including the property covered by its patents. These patents now cover sole rights to
the composition and synthesis of the LB-100 and LB-200 series of drugs. Joint patent applications with the NIH have been filed
for the treatment of glioblastoma multiforme, medulloblastoma, and neuroblastoma. The Company has also filed claims for the use
of certain homologs of both series of drugs for the potential treatment of neurodegenerative diseases such as Alzheimer’s
Disease and Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s Disease), stroke, and traumatic
brain injury and of homologs of the LB-200 series for treatment of serious systemic fungal infections and for the treatment of
common fungal infections of the skin and nails. Other claims cover biomarkers uniquely associated with specific types of cancer
that may provide the bases for assays suitable for cancer detection and patents for development of a tool for screening new compounds
for anti-cancer activity.

Patents for composition of matter and for
several uses of both the LB-100 series (oxabicycloheptanes and –heptenes) and the LB-200 series (histone deacetylase inhibitors;
HDACi) have been filed. Patents for the LB-100 series and the LB-200 series have been filed in the U.S. and widely internationally
(PCT). International filings are currently all pending.

Issued patents are:

LB-100 Series Compounds

Oxabicycloheptanes and Oxabicycloheptenes, Their Preparation
and Use

    Patent

    Priority Date

    Type

    Expiration Date

    US 7,998,957

    Feb 6, 2008

    Composition and Use in Cancer Treatment

    2/20/2030

    US 8,227,473

    Aug 1, 2009

    Composition  and Use in Cancer Treatment

    2/20/2030

    US 8,426,444 Div

    Feb 6, 2008

    Composition and Use in Cancer Treatment

    2/6/2028

Scot J. Foley

U.S. Securities and Exchange Commission

October 8, 2013

Page 4

LB-200 Series Compounds

HDAC Inhibitors

    US 8,143,445
    Oct 1, 2008
    Composition and Use in Cancer Treatment
    8/23/2029

    US 8,455,688 Divisional
    Oct 1, 2008
    Composition and Use in Cancer Treatment
    10/1/2028

LB-100 and LB-200 Series Compounds

Neuroprotective Agents for the Prevention and Treatment of
Neurodegenerative Diseases

    US 8,058,268
    Aug 1, 2009
    Use in Treatment of Multiple CNS Diseases
    12/31/2029

    US 8,329,719 Divisional
    Aug 1, 2009
    Use in Treatment of Multiple CNS Diseases
    7/29/2029

This will acknowledge that the Company is
responsible for the adequacy and accuracy of the disclosure in the filing; staff comments or changes to disclosure in response
to staff comments do not foreclose the Securities and Exchange Commission from taking any action with respect to the filing; and
the Company may not assert staff comments as a defense in any proceeding initiated by the Commission or any person under the federal
securities laws of the United States.

    Very truly yours,

    Lixte Biotechnology Holdings, Inc.

    By:
     /s/ John Kovach

    Name:
    John Kovach

    Title:
    President